long-term function of beta cell allografts in non-uremic type 1 diabetic patients

Conditions: Diabetes Mellitus, Type 1

Summary: the present proof of concept study addresses the following specific aims: the general objectives of this work are: 1. to increase and maintain the functional beta-cell mass after islet transplantation under a condition of low-dose tacrolimus 2. to co-investigate the potential of alternative sites for encapsulated beta-cells

1. aim 1: to increase functional beta cell mass by adding rituximab at first implantation 2. aim 2: to increase functional beta cell mass by adding basilixumab at second implantation 3. aim 3: to assess the influence of down-tapering the tacrolimus dose during posttransplant years 2-5 on these data, on metabolic control, on the prevalence of hypoglycemia and on safety parameters. 4. aim 4: to investigate the potential of the peritoneum and omentum as an alternative site for encapsulated beta-cells. 5. aim 5: to investigate the potential of the brachioradial muscle as an alternative site for encapsulated beta-cells.

Eligibility criteria:
inclusion criteria: * age 18-65 years, male or female, caucasian or not; only subjects \< 50 yrs will be allocated to the rituximab treatment arm * body weight \< 100 kg; patients with a bodyweight of \< 80kg, will receive priority * patients with a bmi ≤ 27 kg/m2 will receive priority * type 1 insulin-dependent diabetes * c-peptide \ 180 mg/dl) * intensive insulin therapy for more than two years, patients with insulin pump during at least 2 months before inclusion will receive priority * patients should have at least one of the following chronic complications of diabetes: * plasma creatinine \ 1 month) outside an episode of illness, despite intake of ace inhibitors; mean systolic blood pressure should be under 130 mmhg and mean diastolic blood pressure under 85 mmhg, when measured at home with ambulatory bp monitoring * moderate or severe non-proliferative or proliferative retinopathy * hypoglycemic unawareness * cooperative and reliable patient giving informed consent by signature exclusion criteria: * smoker * ebv antibody negativity * hiv 1 \& 2 antibody positivity * cmv igm positivity * plasma creatinine ≥ 2 mg/dl and/or albuminuria ≥1000 mg/24 hrs * history of thrombosis or pulmonary embolism * history of malignancy, tuberculosis or chronic viral hepatitis * history of any other serious illness which could be relevant for the protocol * presence of hla antibodies * blood donation within one month prior to screening or during the study * symptoms and/or signs of infection, particularly (present or past) endocarditis, osteomyelitis, past tuberculosis with requirement for therapy * any history of hepatic or neoplastic disease * any history of renal disease (except diabetes) * abnormal liver function tests and /or nmr of liver * hemoglobinopathy * history of any illness that, in the opinion of the investigator, might confound the results of the study or pose additional risks to the patient * pregnancy or use of inadequate contraception by female patients of childbearing potential * use of illicit drugs or overconsumption of alcohol (\> 3 beers/day) or history of drug or alcohol abuse * being legally incapacitated, having significant emotional problems at the time of the study, or having a history of psychiatric disorders * having received antidepressant medications during the last 6 months * having participated the last 12 months or participating in another clinical study

Keywords: diabetes mellitus type 1 pancreatic beta cell transplantation